Part.
Right. Great. Good morning, everyone. Welcome again to TD Cowen's 45th Annual Healthcare Conference, Day One. Thank you very much for coming. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. For our next session, we have a hybrid presentation and Q&A with Tyra, and it's my pleasure to introduce Todd Harris, the CEO and founder. Todd, it's a privilege to have you here. Thanks for being with us.
Thanks for having us, Tyler.
With that, go ahead and get started. Feel free to get started on the presentation, and then we'll get into Q&A afterwards.
All right. Good morning, everyone. Just to kick off, be advised we'll make some forward-looking statements today. We'll tell you a little bit about Tyra. Tyra is a company that has as our lead drug an asset called TYRA-300. We are a structure-based drug design discovery shop. We make our drugs from scratch and a clinical development company today. We have $360 million in cash, and we'll talk about some exciting upcoming milestones that we have towards the end of the presentation. Just to kick it off, though, I want to focus on the target. FGFR3 drives multiple large market opportunities. On the urothelial carcinoma space, there is an addressable population of over 65,000 patients that are FGFR3 positive that could be addressed today with a targeted therapy.
To put that into perspective, that's nearly double the size of the EGFR positive lung cancer market, where osimertinib business is a nearly $6 billion small molecule drug today. Now, a couple of the key indications we're focused on today with phase IIs or about to move into phase II is the intermediate-risk NMIBC market, where there's 70% FGFR3 positivity and 20,000 to 40,000 addressable patients each year. Then the late-line metastatic, where there's a smaller percentage of FGFR3 positivity, but nonetheless about 3,400 patients that could be addressed. At the same time, outside of oncology and genetic conditions, specifically skeletal dysplasias, there are nearly 40,000 kids with open growth plates today that have an FGFR3-related skeletal dysplasia condition. That includes achondroplasia, where there's nearly 3,000 kids today.
This is a very interesting and exciting market as we're seeing vosoritide is reaching nearly $1 billion in sales in this just achondroplasia market alone. An FGFR3 selective drug has the opportunity to address both of these very large markets, and TYRA-300 is our lead FGFR3 drug, potentially best in class over the pan-FGFR inhibitors and others that have tried with the FGFR3 selective space. Today I'm going to talk about each of the three opportunities: the metastatic urothelial, NMIBC, and ACH. We'll start with just a little bit of a breakdown of what FGFR3 positivity means. Either with a cysteine mutation or one of these TACC3 fusions, you end up with constitutive activation of FGFR3 and continuous signaling.
That occurs in mUC and in NMIBC, and there's been an erdafitinib, J&J's drug, that has actually done some great benchmarking and work upfront to show a 35% ORR rate in metastatic, but an 83% CR rate in the NMIBC space with a lower, actually with a lower dose. It is a validated indication. The issue with these and other pan-FGFR drugs is this, and that is the key toxicities associated with FGFR2. You can see here at the top with nearly 70% nail disorders, 63% stomatitis, PPE, central serous retinopathy. Those are our FGFR2-driven toxicities. FGFR1, you see hyperphosphatemia at 76%. These lead to significant dose reductions. One in four patients is going to dose reduce because of the nail issues, one in five due to the stomatitis and the mouth issues. We designed TYRA-300 to be selective for FGFR3 and to spare FGFR2.
One, we used our SNA P chemistry platform, a structure-based drug design approach. We've shared this preclinical data for a few years now, highlighting that we've built in orders of magnitude separation in this cellular assay from FGFR3 activity versus 2, 1, and 4, and did this head-to-head with the pan-FGFR inhibitors that are approved, including Infigratinib, Erdafitinib, just to show how meaningful that separation was. We went into a phase I study, and we read this study out this fall at the TRIPLE meeting in Barcelona. Briefly, what did we learn in this study? We saw a remarkable activity of 54.5% confirmed PR rate versus that 35% rate you see with Erdafitinib. Anti-tumor activity, once we got to our 90 mg dose where we expected IC90 coverage, and generally very well tolerated with infrequent FGFR2 and 1 associated toxicities.
These were the 11 patients that got to 90 mg or above that had FGFR3 positive urothelial. What you can see remarkably is a 100% disease control rate. All of the tumors are shrinking, many of the tumors getting to 30% reduction or more. On the toxicity spectrum, and this is in the 15 patients that saw the 90 mg dose, we saw a remarkable reduction in nail disorders, only one case out of 15, low grade, one case of stomatitis out of 15. While it was grade three, this was actually addressed with no interruptions or reductions. The patient self-resolved in about a week.
Low amounts of PPE, central serous retinopathy, remarkably low amounts of hyperphosphatemia, remarkably low amount of diarrhea, and AST/ALT increase that were on par with erda at this dose, and quite frankly, on par with any of the pan-FGFR inhibitors that have been used in this population, and on par with MAT inhibitors, EGFR inhibitors, RET inhibitors, and TRK inhibitors. This is something you do tend to see. They're asymptomatic, largely low grade, like you see here. Quite excitedly, we had a population treated at lower doses, about 22 patients. That's either a 40 mg or 60 mg dose, which is particularly relevant for the doses we're going to be using in NMIBC and ACH. There, very low amounts of any grade AEs, one ALT increase at the 60 mg dose, but this was actually a patient whose highest ALT level was at their initial baseline scan.
Otherwise, no hyperphosphatemia, otherwise no ALT/ AST, no discontinuations, no reductions. A really relevant dose that is the basis for the phase IIs that we've now opened up. First, in NMIBC, talked about how large this patient population is with 700,000 plus people in the U.S. alone today living with bladder cancer. Now, FGFR3 positivity overall is about 40% to 44%, but in this intermediate-risk NMIBC setting, 70%. We have this very large captive population that could be addressed today. Now, when we think about bladder cancer staging, it's really done by tumor infiltration. NMIBC are these cyst, TA, and T1 tumors that aren't invading the muscle. Intermediate risk is defined by these low- grade TA or T1 lesions for the most part.
These are addressed today somewhat barbarically with these very large telescoping devices that are inserted into the urethra under general anesthesia to cut out and try and remove these tumors surgically. The challenge is that they keep coming back. You see a 30% to 40% recurrence rate despite multiple surgeries. Patients are coming back and needing this again. There are some innovative approaches advancing in development. We've got UroGen, CG Oncology, J&J. All of these are procedure-based approaches, which are going to be attractive and interesting opportunities for patients. When we look at the efficacy of erdafitinib specifically, in the Pretzel, so this is a locally delivered device, about a 90% CR rate. All of these procedures do come, though, with some localized AEs. We're talking about pain, discomfort, desire to urine, urgency, and blood in the urine.
J&J actually looked at an oral approach with erdafitinib before they did the local approach. They saw an 83% CR rate despite using a lower dose of erdafitinib. The systemic toxicities, particularly the hyperphosphatemia, the diarrhea, were reasons they did not continue. In light of the data that I just showed you, that really exceptional tolerability we are seeing with this drug opens up this very exciting space. We are the only ones pursuing at the moment an oral targeted approach for intermediate-risk NMIBC. Contrary to belief by many, the oral opportunity in the urologists economically is actually quite interesting, and it has evolved significantly over the last 15 years, where urologists used to be very procedure-oriented. Increasingly, with the advent of the high-priced oral prostate cancer drugs, in-office dispensaries started to get set up in each of these urologists' offices.
Now 40% of the economics of a community urologist practice is driven by therapy spend, with the majority of that and all of the growth coming from in-office dispensed drugs. As you can see, 25% here. The refresh on this in 2024 is going to be even higher amount of drug therapy revenue. There is a strong interest to do dispensed drugs in the urologist's office, and there is a strong interest from patients to have an oral therapy. We think it's very exciting. We're exploring two different doses, 50 mg and 60 mg, an IND that's now cleared with the expectation of treating our first patient in Q2, and a readout initially that's going to be a three-month CR readout. Really quickly, I'll finish up here before we get into Q&A, Tyler, on ACH. This is a very exciting opportunity. It's a very important condition that's FGFR3-driven.
Short stature, both achondroplasia and hypochondroplasia are amino acid and DNA point mutations that lead to these conditions. If we look specifically at achondroplasia, it's this G380R mutation. It inhibits chondrocyte proliferation and differentiation because of the overactivity or overexpression of FGFR3. That then leads to serious complications in infancy and long-term complications associated with pain. Multiple surgeries, reach, and function as children age. Now, the endpoint that the FDA and industry has set on here has been a surrogate endpoint of annualized height velocity. This is a very measurable endpoint where an average child from age five to 10 is going to grow about 4 cm. per year versus someone without achondroplasia is going to grow about 7.6 cm. per year.
With development now of two different CMP drugs shown on the bottom, they were able to move that average up to 6 cm., not quite to physiologic growth, but move it up meaningfully. Despite increased doses, that is essentially the highest you're going to get on the dose response curve for growth. Infigratinib, however, is a pan-FGFR inhibitor, and as it starts off on its dose response curve, at a very low dose, they're achieving about a 6 cm. per year growth. Now, that dose is meaningfully less than what is used in oncology. It's a relatively modest engagement of FGFR3, and there's certainly evidence that you can move far higher in growth with further target engagement. You see that preclinically, and you even see evidence of this clinically as well.
Our goal and target with this program is really moving the field beyond the 6 centimeter annualized height velocity up to 7.5 cm., potentially even 8.5 cm. with the phase II data that we're going to be collecting. With that, let me just, in the interest of time, fast forward a little bit to the trial design. We're going to be testing four different doses. These correspond to our adult human doses of 10 mg, 20 mg, 30 mg, and 40 mg. We anticipate that as we get to the higher doses here, we're going to be engaging the target upwards of about an IC50. Our estimation with the pan-FGFR inhibitor infigratinib at the dose that they're using, which is here, is probably engaging the target right now at maybe an IC15 to IC20.
Further target engagement, we anticipate, will push the annualized height velocity, which ultimately we hope leads to significant improvements in all of the clinical sequelae that we talked about. Beyond achondroplasia, there's some really large opportunities, particularly when we look at hypochondroplasia, Léri-Weill dyschondrosteosis. This is a Schoch's mutation that has a direct impact on driving FGFR3 overexpression, as well as idiopathic short stature. With that, what you can expect from us is coming up shortly our first patient dose in the ACON study, next quarter a first patient dose in our NMIBC study, continued enrollment in that mUC study that we talked about. We do have other assets as well with TYRA-430 and TYRA-200 that are advancing the clinic. With that, let's get into questions, Tyler.
Great, Todd. Thank you very much for the.
I'll sit by you for that too, if you don't mind.
Sounds good. Thank you very much for that presentation. Never disappoint with your slides. Some good new ones in there. I encourage you guys to download it from the website when it becomes available. We'll start with bladder cancer and then move into achondroplasia. You mentioned the SURF301 data that you guys presented at the TRIPLE meeting, as shown on the slides. Really encouraging early evidence of efficacy, and with a lot of those FGFR1, 2 related tox events significantly decreased versus erda. I wanted to ask about the recent Lilly data update at ASCO GU. Not too many people, I think, are actually aware of it, but it's from LOXO-435, the only other oral FGFR3 selective inhibitor in the clinic.
Maybe you could touch upon that data set, how you think it compares to what you guys showed with TYRA-300 and what the points of differentiation might be.
Yeah. First off, obviously options for patients is what we all celebrate. It is great to have more data and effort in the space. I think we were, with what we saw in the data, I think it was the best possible outcome for Tyra. I think it highlighted, one, just how challenging it is to generate good data in this space. Their efficacy was on par with erda at about 41%, and compare that to the 54.5% confirmed ORR that we saw. They saw a really high rate of diarrhea at over 70%. They saw a high rate of hyperphosphatemia.
The selectivity that they saw preclinically, I think they're starting to move away from that as they move into the clinic. We anticipated that may be the case just because they needed so much drug on board. It's likely due to some efflux challenges they have with the drug that they just started to lose some of that selectivity in the clinic. Our relative selectivity AE profile in comparison, we felt just looked exceptional. I think it creates a ton of daylight between us and any competition that's looking at the FGFR3 space. We also confirmed that they're not moving it forward in non-muscle invasive bladder cancer, achondroplasia, where some of these bigger markets are. I think that's likely just due to the AE profile and the challenges they're seeing with the drug.
Yeah, it's a great outcome, great validation for the data set that we put up. Obviously, that's a group that's got money to invest and has done some great drug development in the past. We're pleased overall with the comparison.
Okay. Great. The SURF302 trial evaluating TYRA-300 in intermediate-risk NMIBC, as you mentioned, three months is a critical time point to look at early efficacy. Maybe you could talk about when we might see that data and what you would hope to show at three months.
Yeah. We're not guiding specifically to data disclosure timelines yet, but I think one of the things you can expect, and this is a setup for us generally, because we go throughout the year, we're going to be enrolling patients. We're going to have an early look at safety, tolerability, some early looks at efficacy.
I think as that data mature, likely as we get into early next year, will be that opportunity for us to highlight the safety efficacy in each of the populations we're pursuing here. Both achondroplasia, NMIBC, and further maturity in our mUC data can all likely read out at a similar timeframe. Our expectation, I think that's what investors want to see from us at this. I think that's what we want to see is what does this safety look like in an otherwise relatively healthy child or a more healthy patient that has intermediate risk disease, as opposed to obviously the patient population that we just read out, which had greater than three lines of therapy, over age 65, and a lot of comorbidities associated with their disease.
I think it's important for us to be able to have these data sets independently, and I think they're going to mature on it at a similar timeframe. That way we'll be able to speak to quite a bit, call it early next year.
Okay. Again, at that three months, I guess the goal would just be to try to replicate what erda has shown in the small data set.
Yeah. When we talk to KOLs and advisors in the space, anything north of 70% CR rate is a success, a big success. What we really want to balance is the most tolerable profile with the dose that we choose that achieves that 70% or greater.
Okay. Based upon the number of patients and the opportunity, it makes sense that you would choose intermediate-risk NMIBC over metastatic urothelial carcinoma or late-stage bladder cancer.
Why choose intermediate risk as opposed to high grade or high risk? May you pursue that in the future?
Yeah. Certainly, we're going to look to pursue that in the future. There is plenty of FGFR3 positivity, albeit at a lower rate than you see in the intermediate risk space. There's a little bit more competition there today, but really we would be the only oral pursuing that. It is certainly something we'll look at in the future. We're looking at the intermediate risk opportunity as potentially our fastest path today, and it's very enriched. For the precious R&D dollars that we spend, we've prioritized that indication first.
Okay. That's helpful.
In intermediate-risk NMIBC, for anyone who's done work in the space, you're used to doctors talking about catheters and installations, and you touched on this briefly, but can you just elaborate on the use of oral therapies or things that don't need to be delivered via installation in the bladder currently and how you expect that to evolve over time?
Yeah. With bladder cancer in the urologist's office, there's really no options, but that's very different than prostate cancer. I'm looking at Adele here in the audience who recently joined our board, who commercialized a drug called ORGOVYX. If you look at a lot of the growth that's happened in the urologists' practice economics, it's actually been ORGOVYX that's driven a lot of in-office dispensing. This is moving a procedure to an oral drug. It's more friendly for the patient.
As these in-office dispensaries have now been set up in the urologists, it actually makes practical economic sense as well for these urologists to prescribe. This is a big trend that's evolved over five to 10 years in prostate cancer. These are the same doctors. It just hasn't happened yet in bladder cancer because no one's had a drug. Being the first targeted therapy, I think the practice economics are very well set up for them to want to prescribe, for patients to want to have a drug like this. Just a matter of getting it approved.
Yeah. Can you just elaborate on the practice economics?
I guess obviously they save time if they're writing a prescription for an oral therapy, but I guess if you've got some of these major academic centers and use specialty pharmacy, you allow them to distribute it and then they make money off the therapy that way, or what are all the ways that they?
Yeah. There was a specialty network, UroGPO, did do a call that I think that's publicly available recently with Chris Raymond that highlighted a couple of points that when you prescribe a drug, there is some management of that patient. And so being able to set up an in-office dispense program allows the physician to obviously participate in the economics, have the benefit of that while they're managing any of the AEs or other elements of that drug dispensing.
That is important because it really then aligns them with the patient and keeping the patient and not just having a procedure or a buy-and-bill product be the sort of main motivating factor economically. With that alignment, I think it takes away the disincentives. It creates some incentives. Certainly then when an oral is best for patient care, I think it is now very well aligned for urologists to want to be able to deliver that.
Can you talk about what you expect the dose to be for NMIBC moving forward, how that might compare to mUC and what the next steps for mUC are?
Yeah. We saw clear evidence from the way that J&J did erdafitinib development that a lower dose worked really well here. Even though they started at 8 mg or 9 mg, they realized it was not very tolerable. They moved to 6 mg.
They saw an 83% CR rate. They even had patients dosing down to 4 mg. Why is that? Many TKIs, and this is true from the preclinical data we've seen with TYRA- 300, tend to accumulate in the bladder. You get higher bladder concentration versus plasma. You also have more likely a single driver mutation driving these small lesions than multiple drivers that may be driving a metastatic disease. I think those two points lead to some very strong evidence that a lower dose can be very effective.
Okay. As we think about metastatic bladder mUC moving forward in the median PFS, what do you need to show there as you see the additional data to get confidence to move into a pivotal program?
Yeah. What we're doing right now is we are testing slightly higher doses, 100 mg. We're even testing 110mg.
These have more exposure, meaningfully more exposure. We're just testing the hypothesis. We've pushed the efficacy really more than anyone else has seen, so can we push it further? That's an important question. At the same time, we're just maturing the data at 90, 100, and 110. And what that will allow us to see is what does our duration of response, for example, look like relative to erdafitinib? Internally, we're very confident. We've always had a hypothesis that the tolerability should drive improvement in durability, and we retain that confidence. The data we're going to collect this year will help us know just how much better and really then help us think about how do we design a phase III for success.
Great. Let's move to achondroplasia for the last few minutes. Yep.
Are we talking the erdafitinib data? Infigratinib or erdafitinib? Sorry, you said it. Yeah.
Yes. The duration that they reported was, I think, around seven months, but many of the patients are actually coming off of drug due to tolerability challenges. They have not done a data report since the 2023 SUO. Given that a drug drives a CR rate upfront, you'd expect plenty of drug to be on board to retain durability past that. I would expect if a patient can stay on drug with an FGFR3 inhibitor, you're going to see really nice duration out at 12 months and 24 months as long as they're staying on drug.
You also were talking about low incidences of FGFR positivity in the high risk. Is that because patients who are in the median risk can eventually progress through biology of the tumor changes and you've got a different driver? There's a different biology just at the very start.
Yeah.
I mean, this is all a bit of a hypothesis and conjecture, but you look at from low grade to high grade to metastatic, you see FGFR3 positivity go down. To me, that suggests that FGFR3 as a mutation is enough to drive these small lesions. As they become more invasive, they're likely probably picking up some additional mutations that are necessary for metastasis and further progression. That may be true of even muscle invasiveness and moving into high risk. That being said, even in high risk, the positivity is still pretty high, 40% plus FGFR3 positivity. It's not until you get to the muscle invasive and the metastatic that it moves down to 20% and maybe down to 15%.
Do you have additional drivers at that point that's become higher and higher risk?
I'm not sure that there's great data to suggest that from intermediate risk to high risk, you increase the amount of driver mutations, but there are obviously a shift in the population towards other mutations.
Okay. Achondroplasia. The BEACH 301 trial, phase II, achondroplasia, beginning dosing. How soon could we expect data? I presume it'll be from the sentinel cohorts initially?
Yeah. Twelve patients, sentinel cohort, where we're going to be looking at three patients at each of the four doses. That's a key safety readout, of course. Each of these three patients, once enrolled, there'll be a DLT period of 30 days before we advance and escalate up. That gets us through the first twelve patient sentinels.
Once we've cleared a dose on the sentinel, we can open up and start treatment on these further buildout of cohort one and two, either naive or prior drug-treated. That first data set will be a clear signal around safety, as well as initially six months and then 12 months. This would be very much a dose response curve analysis, looking at annualized height velocity. The benchmarks are pretty clear here, both on the natural history, and you can even look at the infigratinib data to say we would expect meaningfully higher annualized height velocity, especially at the cohort, our dose level three or dose level four when we look at those kids on treatment.
If there's no baseline run-in, are you comparing them to age-matched historical controls, or?
Yeah, that's exactly right.
If you look at the age group we're testing, five to 10, with 1,000 plus kids measured in the CLARITY data set, you can see that they're going to grow on average 4 cm. per year. Moving meaningfully beyond that will be, I think, clear evidence of activity.
Do you think we could get some of this early data by the end of the year, or?
Yeah. Again, not guiding specific on timelines. I think we'll be evaluating some safety throughout the year. That's going to be important. I think expecting some of the early efficacy towards the end of the year. By early next year, I think we can expect that the 12 patients we would largely have. We'll likely report out that broader data set together as opposed to dribble data out.
Got it.
You had some great slides on this looking at height velocity versus the other programs on the market or in later stage development, but you went through it quickly, so I just want to double-tap on it. Just the opportunity for improvement in height velocity, right? There's been this some people make comments that there's not much room to improve. You're going to take them to height velocity levels that are kind of above the normal range that are too high. They're going to be growing too quickly, which obviously would be tremendous for this population to grow significantly more in general. Can you just talk about that and the room for improvement?
Yeah. Look, I think we now have a ton of experience with vosoritide that's getting to nearly 6 centimeters per year.
There are whole countries that will not pay for it because they just do not see the benefit with the marginal centimeter, centimeter and a half that you are getting. At the same time, some of the patient forms in certain countries, like the ALPI form in Spain, are talking about adding limb lengthening surgery on top of vosoritide. That is obviously a relatively barbaric treatment you would love to avoid. There is a lot of enthusiasm, not just getting to 7.6 cm., which would be closer to physiologic growth, but even catch-up growth at 8.5 cm. safely, especially for kids that are going to be starting on the treatment, not from age zero. There is plenty of enthusiasm on the potential benefits that could come. I think there is just a ton of now history with 8.5 cm. on average being very safe.
That's what you're going to see with growth hormone, for example, in this population. Kids without FGFR3-driven short stature that have gone on Vosoritide have seen 8.5 cm. annualized height velocity at 12 months. The physicians and families are very, very excited. That's a great outcome. That's sort of the benchmark. We know that if we push FGFR3 inhibition even further, there are case studies of kids, not necessarily with dwarfism, but with tumors that go on Erdafitinib that will see their growth change from 7.6 cm. to 19 cm. during a nine-month period that they're on treatment. They're getting this rapid growth, but that will come with complications. It can come with some fractures and other issues.
We're not trying to push it there, but getting a very meaningful outcome with catch-up growth over multiple years, we think about that eight and a half centimeter benchmark being really meaningful.
Okay. We're up on time, but maybe just a couple of quick ones. Beyond achondroplasia, how soon might you guys expand into additional bone dysplasia such as hypochondroplasia or Léri-Weill, something that was the first time I heard it?
Léri-Weill dyschondrosteosis, yeah. Exactly. Yeah, yeah. No, we are actually planning to move quite rapidly. What's nice about this first study, this is going to give us safety and dosing information, but that dose information will be very relevant for Léri-Weill and for hypochondroplasia. There's no more preclinical work for us to do. We would go straight into it.
Essentially, once we have some dose information with ACH, we're going to be starting that preparation. That's going to get, that will obviously, from a competitive perspective, put us a lot closer to where some of the competitors are in their development paths.
Wonderful. Todd, to close out, what do you believe is the most underappreciated aspect of the Tyra story by investors right now?
I think the quality of the molecule that we have has now really been validated with LOXO's data. All the pan-FGFR data is out there. And then just the sheer size of these opportunities. This is going to be an exciting few years for us.
Wonderful. Thank you very much.
Thanks, Tyra.
Thanks, guys. Welcome again to TD Cowen's 45th Tyra. And it's my pleasure to introduce Todd Harris, the CEO and founder. And Todd, it's a privilege to have you here.
Thanks for being with us.
Thanks for having us, Tyler. With that, go ahead and feel free to get started in the presentation, and then we'll get into Q&A afterwards. All right. Good morning, everyone. Just to kick off, be advised we'll make some forward-looking statements today. We'll tell you a little bit about Tyra. Tyra is a company that has as our lead drug an asset called TYRA-300. We are a structure-based drug design discovery shop. We make our drugs from scratch and a clinical development company today. We have $360 million in cash, and we'll talk about some exciting upcoming milestones that we have towards the end of the presentation. Just to kick it off, though, I want to focus on the target. FGFR3 drives multiple large market opportunities.
On the urothelial carcinoma space, there is an addressable population of over 65,000 patients that are FGFR3 positive that could be addressed today with a targeted therapy. To put that into perspective, that's nearly double the size of the EGFR-positive lung cancer market, where osimertinib is a nearly $6 billion small molecule drug today. Now, a couple of the key indications we're focused on today with phase II's or about to move into phase II is the intermediate risk NMIBC market, where there's 70% FGFR3 positivity and 20,000 to 40,000 addressable patients each year. And then the late-line metastatic, where there's a smaller percentage of FGFR3 positivity, but nonetheless, about 3,400 patients that could be addressed. At the same time, outside of oncology and genetic conditions, specifically skeletal dysplasias, there are nearly 40,000 kids with open growth plates today that have an FGFR3-related skeletal dysplasia condition.
That includes achondroplasia, where there's nearly 3,000 kids today. This is a very interesting and exciting market as we're seeing vosoritide is reaching nearly $1 billion in sales in this just achondroplasia market alone. An FGFR3 selective drug has the opportunity to address both of these very large markets. TYRA- 300 is our lead FGFR3 drug, potentially best in class over the pan-FGFR inhibitors and others that have tried with the FGFR3 selective space. Today, I'm going to talk about each of the three opportunities: the metastatic urothelial, NMIBC, and ACH. We'll start with just a little bit of a breakdown of what FGFR3 positivity means. Either with a cystine mutation or one of these TACC3 fusions, you end up with constitutive activation of FGFR3 and continuous signaling. That occurs in mUC and in NMIBC.
There's been an erdafitinib, J&J's drug, that has actually done some great benchmarking and work upfront to show a 35% ORR rate in metastatic, but an 83% CR rate in the NMIBC space, actually with a lower dose. It is a validated indication. The issue with these and other pan-FGFR drugs is this. That is the key toxicities associated with FGFR2. You can see here at the top with nearly 70% nail disorders, 63% stomatitis, PPE, central serous retinopathy. Those are our FGFR2-driven toxicities. Then FGFR1, you see hyperphosphatemia at 76%. These lead to significant dose reductions. One in four patients is going to dose reduce because of the nail issues. One in five due to the stomatitis and the mouth issues. We designed TYRA-300 to be selective for FGFR3 and to spare FGFR2.
One, we used our SNAP chemistry platform, a structure-based drug design approach. We've shared this preclinical data for a few years now, highlighting that we built in orders of magnitude separation in this cellular assay from FGFR3 activity versus two, one, and four, and did this head-to-head with the pan-FGFR inhibitors that are approved, including infigratinib, erdafitinib, just to show how meaningful that separation was. We went into a phase I study, and we read this study out this fall at the TRIPLE meeting in Barcelona. Briefly, what did we learn in this study? We saw a remarkable activity of 54.5% confirmed PR rate versus that 35% rate you see with Erdafitinib antitumor activity once we got to our 90 mg dose where we expected IC90 coverage and generally very well tolerated with infrequent FGFR2 and one associated toxicities.
These were the 11 patients that got to 90 mg or above that had FGFR3 positive urothelial. What you can see remarkably is 100% disease control rate. All of the tumors are shrinking. Many of the tumors getting to 30% reduction or more. On the toxicity spectrum, and this is in the 15 patients that saw the 90 mg dose, we saw a remarkable reduction in nail disorders. Only one case out of 15, low grade. One case of stomatitis out of 15. While it was grade three, this was actually addressed with no interruptions or reductions. The patient self-resolved in about a week.
Low amounts of PPE, central serous retinopathy, remarkably low amounts of hyperphosphatemia, remarkably low amount of diarrhea, and AST/ALT increase that were on par with erda at this dose and, quite frankly, on par with any of the pan-FGFR inhibitors that have been used in this population and on par with MET inhibitors, EGFR inhibitors, RET inhibitors, and TRACC inhibitors. This is something you do tend to see. They're asymptomatic, largely low grade, like you see here. Quite excitedly, we had a population treated at lower doses, about 22 patients. That's either a 40 mg or 60 mg dose, which is particularly relevant for the doses we're going to be using in NMIBC and ACH. There, very low amounts of any grade AEs. One ALT increase at the 60 mg dose, but this was actually a patient whose highest ALT level was at their initial baseline scan.
Otherwise, no hyperphosphatemia, otherwise no ALT/ AST, no discontinuations, no reductions. A really relevant dose that is the basis for the phase IIs that we've now opened up. First, in NMIBC, talked about how large this patient population is with 700,000 plus people in the U.S. alone today living with bladder cancer. Now, FGFR3 positivity overall is about 40% to 44%, but in this intermediate-risk NMIBC setting, 70%. We have this very large captive population that could be addressed today. Now, when we think about bladder cancer staging, it's really done by tumor infiltration. NMIBC are these cyst, TA, and T1 tumors that aren't invading the muscle. Intermediate risk is defined by these low-grade TA or T1 lesions for the most part.
These are addressed today somewhat barbarically with these very large telescoping devices that are inserted into the urethra under general anesthesia to cut out and try and remove these tumors surgically. The challenge is that they keep coming back. You see a 30% to 40% recurrence rate despite multiple surgeries. Patients are coming back and needing this again. Now, there are some innovative approaches advancing in development. We've got UroGen, CG Oncology, J&J. All of these are procedure-based approaches, which are going to be attractive and interesting opportunities for patients. When we look at the efficacy of erdafitinib specifically in the Pretzels, this is a locally delivered device, about a 90% CR rate. All of these procedures do come, though, with some localized AEs. We're talking about pain, discomfort, desire to urinate, urgency, and blood in the urine.
J&J actually looked at an oral approach with erdafitinib before they did the local approach. They saw an 83% CR rate despite using a lower dose of erdafitinib. The systemic toxicities, particularly the hyperphosphatemia, the diarrhea, were reasons they didn't continue. In light of the data that I just showed you, that really exceptional tolerability we're seeing with this drug opens up this very exciting space. We are the only ones pursuing at the moment an oral targeted approach for intermediate-risk NMIBC. Contrary to belief by many, the oral opportunity in the urologists economically is actually quite interesting. It's evolved significantly over the last 15 years, where urologists used to be very procedure-oriented. Increasingly, with the advent of the high-priced oral prostate cancer drugs, in-office dispensaries started to get set up in each of these urologists' offices.
Now, 40% of the economics of a community urologist practice is driven by therapy spend, with the majority of that and all of the growth coming from in-office dispensed drugs. As you can see, 25% here. The refresh on this in 2024 is going to be even higher amount of drug therapy revenue. There is a strong interest to do dispensed drugs in the urologist's office, and there is a strong interest from patients to have an oral therapy. We think it is very exciting. We are exploring two different doses, 50 mg and 60 mg, an IND that is now cleared with the expectation of treating our first patient in Q2, and a readout initially that is going to be a three-month CR readout. Really quickly, I will finish up here before we get into Q&A, Tyler, on ACH. This is a very exciting opportunity. It is a very important condition that is FGFR3-driven.
Short stature, both achondroplasia and hypochondroplasia are amino acid and DNA point mutations that lead to these conditions. If we look specifically at achondroplasia, it's this G380R mutation. It inhibits chondrocyte proliferation and differentiation because of the overactivity or overexpression of FGFR3. That then leads to serious complications in infancy and long-term complications associated with pain. Multiple surgeries, reach, and function as children age. Now, the endpoint that the FDA and industry has set on here has been a surrogate endpoint of annualized height velocity. This is a very measurable endpoint where an average child from age five to 10 is going to grow about 4 cm. per year versus someone without achondroplasia is going to grow about 7.6 cm. per year.
With development now of two different CMP drugs shown on the bottom, they were able to move that average up to 6 cm., not quite to physiologic growth, but move it up meaningfully. Despite increased doses, that is essentially the highest you're going to get on the dose response curve for growth. Infigratinib, however, is a pan-FGFR inhibitor, and as it starts off on its dose response curve, at a very low dose, they're achieving about a 6 cm. per year growth. Now, that dose is meaningfully less than what is used in oncology. It's a relatively modest engagement of FGFR3. There's certainly evidence that you can move far higher in growth with further target engagement. You see that preclinically, and you even see evidence of this clinically as well.
Our goal and target with this program is really moving the field beyond the 6 cm. annualized height velocity up to 7.5 cm., potentially even 8.5 cm. with the phase II data that we're going to be collecting. With that, let me just, in the interest of time, fast forward a little bit to the trial design. We're going to be testing four different doses. These correspond to our adult human doses of 10 mg, 20 mg, 30 mg , and 40 mg. We anticipate that as we get to the higher doses here, we're going to be engaging the target upwards of about an IC50. Our estimation with the pan-FGFR inhibitor infigratinib at the dose that they're using, which is here, is probably engaging the target right now at maybe an IC15 to IC20.
Further target engagement, we anticipate it'll push the annualized height velocity, which ultimately we hope leads to significant improvements in all of the clinical sequelae that we talked about. Beyond achondroplasia, there's some really large opportunities, particularly when we look at hypochondroplasia, Léri-Weill dyschondrosteosis. This is a shock mutation that has a direct impact on driving FGFR3 overexpression, as well as idiopathic short stature. With that, what you can expect from us is coming up shortly our first patient dose in the ACON study, next quarter a first patient dose in our NMIBC study, continued enrollment in that mUC study that we talked about. We do have other assets as well with TYRA-430 and TYRA-200 that are advanced in the clinic. With that, let's get into questions, Tyler.
Great, Todd. Thank you very much for the.
I'll sit by you for that too, if you don't mind.
Sounds good. Thank you very much for that presentation. Never disappoint with your slides. Some good new ones in there. I encourage you guys to download it from the website when it becomes available. We'll start with bladder cancer and then move into achondroplasia. You mentioned the SURF301 data that you guys presented at the TRIPLE meeting, as shown on the slides. Really encouraging early evidence of efficacy. With a lot of those FGFR1, 2 related tox events significantly decreased versus erda. I wanted to ask about the recent Lilly data update at ASCO GU. Not too many people, I think, are actually aware of it, but it's from LOXO-435, the only other oral FGFR3 selective inhibitor in the clinic.
Maybe you could touch upon that data set, how you think it compares to what you guys showed with TYRA-300 and what the points of differentiation might be.
Yeah. Look, first off, obviously, options for patients is what we all celebrate. It is great to have more data and effort in the space. I think we were, with what we saw in the data, I think is a best possible outcome for Tyra. I think it highlighted, one, just how challenging it is to generate good data in this space. Their efficacy was on par with erda at about 41% and compare that to the 54.5% confirmed ORR that we saw. They saw a really high rate of diarrhea at over 70%. They saw a high rate of hyperphosphatemia.
The selectivity that they saw preclinically, I think they're starting to move away from that as they move into the clinic. We anticipated that may be the case just because they needed so much drug on board. It's likely due to some efflux challenges they have with the drug that they just started to lose some of that selectivity in the clinic. Our relative selectivity AE profile in comparison, we felt just looked exceptional. I think it creates a ton of daylight between us and any competition that's looking at the FGFR3 space. We also confirmed that they're not moving it forward in non-muscle invasive bladder cancer or achondroplasia where some of these bigger markets are. I think that's likely just due to the AE profile and the challenges they're seeing with the drug.
Yeah, it's a great outcome, great validation for the data set that we put up. Obviously, that's a group that's got money to invest and has done some great drug development in the past. We're pleased overall with the comparison.
Okay. Great. The SURF302 trial evaluating TYRA-300 in intermediate-risk NMIBC, as you mentioned, three months is a critical time point to look at early efficacy. Maybe you could talk about when we might see that data and what you would hope to show at three months.
Yeah. We're not guiding specifically to data disclosure timelines yet, but I think one of the things you can expect, and this is a setup for us generally, because we go throughout the year, we're going to be enrolling patients. We're going to have an early look at safety, tolerability, some early looks at efficacy.
I think as that data mature, likely as we get into early next year, will be that opportunity for us to highlight the safety efficacy in each of the populations we're pursuing here. Both achondroplasia, NMIBC, and further maturity in our mUC data can all likely read out at a similar timeframe. Our expectation, I think that's what investors want to see from us at this. I think that's what we want to see is what does this safety look like in an otherwise relatively healthy child or a more healthy patient that has intermediate risk disease, as opposed to obviously the patient population that we just read out, which had greater than three lines of therapy, over age 65, and a lot of comorbidities associated with their disease. I think it's important for us to be able to have these data sets independently.
I think they're going to mature on it at a similar timeframe. That we'll be able to speak to quite a bit come, call it, early next year.
Okay. Again, at that three months, I guess the goal would just be to try to replicate what erda has shown in the small data set.
Yeah. When we talk to KOLs and advisors in the space, anything north of 70% CR rate is a success, a big success. What we really want to balance is the most tolerable profile with the dose that we choose that achieves that 70% or greater.
Okay. Based upon the number of patients and the opportunity, it makes sense that you would choose intermediate-risk NMIBC over metastatic urothelial carcinoma or late-stage bladder cancer. Why choose intermediate risk as opposed to high-grade or high-risk?
May you pursue that in the future.